My research objectives are to develop in vitro and animal model systems to allow key biological and molecular features of human leukemic hematopoiesis to be identified and reproduced, and to allow assessment of the effects of manipulating leukemic stem cell populations under defined conditions. At present, our efforts are focused on chronic myeloid leukemia, a disease with an annual incidence of 1 per 100,000 and curable in only a limited number of cases, primarily with high dose therapy and a sibling bone marrow transplant.

Chronic myeloid leukemia (CML) arises in a pluripotent hematopoietic stem cell as a result of a specific rearrangement of the BCR gene on chromosome 22 and the c-ABL protooncogene on chromosome 9. This rearrangement results in the formation of the Ph chromosome and a novel BCR-ABL fusion gene which encodes a protein with oncogenic properties. Although the specific molecular pathways by which BCR-ABL mediates its biological effects to cause CML remain largely unknown, a specific inhibitor of the BCR-ABL kinase is now showing great clinical promise and provides a unique experimental tool to test how this gene alters stem cell function.

We have recently developed methods for purifying both leukemic and residual normal stem cells from patients with CML. This has allowed us to analyze their biological and molecular properties and to compare them to BCR-ABL-transduced primary human and murine hematopoietic cells. An early outcome of this effort has been our discovery that the BCR-ABL oncogene activates an autocrine growth mechanism selectively in primitive hematopoietic cells. More recently we have found that this oncogene can also cause hematopoietic lineage switching when it is overexpressed in transduced hematopoietic cells.